title: PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy.
abstract: Short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay (SHORT) syndrome is a developmental disorder with an unknown genetic cause and hallmarks that include insulin resistance and lack of subcutaneous fat. We ascertained two unrelated individuals with SHORT syndrome, hypothesized that the observed phenotype was most likely due to de novo mutations in the same gene, and performed whole-exome sequencing in the two probands and their unaffected parents. We then confirmed our initial observations in four other subjects with SHORT syndrome from three families, as well as 14 unrelated subjects presenting with syndromic insulin resistance and/or generalized lipoatrophy associated with dysmorphic features and growth retardation. Overall, we identified in nine affected individuals from eight families de novo or inherited PIK3R1 mutations, including a mutational hotspot (c.1945C>T [p.Arg649Trp]) present in four families. PIK3R1 encodes the p85α, p55α, and p50α regulatory subunits of class IA phosphatidylinositol 3 kinases (PI3Ks), which are known to play a key role in insulin signaling. Functional data from fibroblasts derived from individuals with PIK3R1 mutations showed severe insulin resistance for both proximal and distal PI3K-dependent signaling. Our findings extend the genetic causes of severe insulin-resistance syndromes and provide important information with respect to the function of PIK3R1 in normal development and its role in human diseases, including growth delay, Rieger anomaly and other ocular affections, insulin resistance, diabetes, paucity of fat, and ovarian cysts.
authors.affiliation: Equipe d'Accueil 4271, Génétique des Anomalies du Developpement, Université de Bourgogne, F-21079 Dijon, France. christel.thauvin@chu-dijon.fr
authors.forename: Christel
authors.initials: C
authors.lastname: Thauvin-Robinet
authors.forename: Martine
authors.initials: M
authors.lastname: Auclair
authors.forename: Laurence
authors.initials: L
authors.lastname: Duplomb
authors.forename: Martine
authors.initials: M
authors.lastname: Caron-Debarle
authors.forename: Magali
authors.initials: M
authors.lastname: Avila
authors.forename: Judith
authors.initials: J
authors.lastname: St-Onge
authors.forename: Martine
authors.initials: M
authors.lastname: Le Merrer
authors.forename: Bernard
authors.initials: B
authors.lastname: Le Luyer
authors.forename: Delphine
authors.initials: D
authors.lastname: Héron
authors.forename: Michèle
authors.initials: M
authors.lastname: Mathieu-Dramard
authors.forename: Pierre
authors.initials: P
authors.lastname: Bitoun
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Petit
authors.forename: Sylvie
authors.initials: S
authors.lastname: Odent
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
authors.forename: Damien
authors.initials: D
authors.lastname: Picot
authors.forename: Virginie
authors.initials: V
authors.lastname: Carmignac
authors.forename: Julien
authors.initials: J
authors.lastname: Thevenon
authors.forename: Patrick
authors.initials: P
authors.lastname: Callier
authors.forename: Martine
authors.initials: M
authors.lastname: Laville
authors.forename: Yves
authors.initials: Y
authors.lastname: Reznik
authors.forename: Cédric
authors.initials: C
authors.lastname: Fagour
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Nunes
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Capeau
authors.forename: Olivier
authors.initials: O
authors.lastname: Lascols
authors.forename: Frédéric
authors.initials: F
authors.lastname: Huet
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
authors.forename: Corinne
authors.initials: C
authors.lastname: Vigouroux
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Rivière
mesh_terms: D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020022:Genetic Predisposition to Disease; D005865:Gestational Age; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006130:Growth Disorders / Q000235:genetics*; D006801:Humans; D006934:Hypercalcemia / Q000235:genetics*; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D008659:Metabolic Diseases / Q000235:genetics*; D009154:Mutation; D009397:Nephrocalcinosis / Q000235:genetics*; D010375:Pedigree; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose